The present invention relates to an aerosol composition. In particular the present invention relates to an aerosol composition in the form of a suspension comprising liquid propellant and particulate material.
Effective use of an aerosol composition in the form of a suspension usually requires the suspension to comprise a uniform dispersion of particulate matter in order to ensure the production of an aerosol of known components in known amounts. Inhomogeneous dispersions can occur due to poor dispersibility of the particulate matter in the propellant and/or a tendency of the particulate matter to aggregate and possibly even to aggregate irreversibly.
Aerosol compositions comprising particulate matter in the form of a suspension can be used for the delivery of a number of active agents. A particular application comprises pharmaceutical suspensions for administration of a drug in particulate form.
An example of a pharmaceutical application of a particulate-containing aerosol composition is inhaler suspensions. Inhaler suspensions are used for delivery of a particulate medicament to the lungs or upper airway passages. Suitably the suspension is contained in a container fitted with a metering valve. A known dose can thus be administered on each occasion of use. Such containers can be convenient to use and are readily portable.
Such a metered dose inhaler conventionally consists of a pressurised container which has a metering valve of fixed volume to measure individual doses of a suspension of medicament held in the container. In order to ensure the administration of an accurate dose of suspended particulate medicament it is essential that the suspension is consistently and homogeneously dispersed and the valve performance is reproducible and effective throughout the life of the container. The suspension conventionally comprises medicament particles dispersed in a liquefied gas which in use acts as a propellant. On depressing the valve stem of the metering valve the propellant fraction of the metered dose rapidly vaporises so as to aerosolise the suspended particulate medicament which is then inhaled by the user.
Traditionally, chlorofluorocarbons such as CFC-11, CFC-12 and CFC-114 have been employed as propellants in metered dose inhalers. A particulate medicament intended for pulmonary administration needs to have a particle size with a median aerodynamic diameter between about 0.05 xcexcm and about 11 xcexcm. This range of size of medicament particle is important in inhalers. Larger particles will not necessarily or readily penetrate into the lungs and smaller sized particles are readily breathed out. However, particles between about 0.05 xcexcm and about 11 xcexcm can possess a high surface energy and can therefore be difficult to disperse initially in the propellant, and once dispersed can exhibit a tendency to aggregate undesirably and rapidly, leading eventually to irreversible aggregation of the particles. In the case of CFC as a propellant this problem was overcome by the addition of a surfactant soluble in the CFC which coats the medicament particles and prevents aggregation by steric hindrance. The presence of surfactant is also believed to be an aid to valve performance. In practice medicament particles were homogenised in the liquid CFC-11 with the inclusion of a propellant soluble surfactant such as lecithin, oleic acid or sorbitan trioleate. The resulting bulk suspension was dispensed into individual metered dose inhalers and a high vapour pressure propellant such as liquefied gas CFC-12/CFC-114 added. Such arrangements proved satisfactory in use, although the added surfactant could adversely affect the perceived taste of the inhaler in use. For example oleic acid could impart a bitter taste.
In recent years the detrimental effect of chlorofluorocarbons on the ozone layer in the earth""s stratosphere has become apparent. The continued use of CFC has therefore become unacceptable and in some instances has been banned by local regulations.
Alternative propellants which share some similar physical properties to those of previously used CFC propellants and which have been suggested for use in metered dose inhalers are hydrofluoroalkanes, notably HFA-134a and HFA-227. Problems however exist on attempting to formulate the hydrofluoroalkanes into an aerosol composition such as an inhaler suspension. Firstly, the acceptable surfactants employed in CFC based suspensions are not sufficiently soluble in hydrofluoroalkanes to prevent irreversible aggregation of the particulate medicament occurring. Secondly, neither HFA-134a nor HFA-227 is a liquid at an acceptable temperature so that bulk homogenisation with particulate material prior to filling into individual pressured containers is only possible if carried out under pressure.
A number of proposals have been made in an attempt to employ hydrofluoroalkanes as the propellant in pressurised metered dose inhalers for example a patent specification (WO 92/06675) in the name of Minnesota Mining and Manufacturing Company suggests the use of non-volatile co-solvents to modify the solvent characteristics of the hydrofluoroalkane propellant and thereby increase the solubility and hence permit the use of the surfactants traditionally employed in CFC based metered dose inhalers. The presence of the co-solvent however may result in less desirable aerosol properties. Moreover the alcohol nonvolatile co-solvents suggested can impart an unpleasant sharp taste.
Patent specifications (WO 91/11173 and WO 92/00061) in the name of Fisons suggest the use of alternative surfactants which are sufficiently soluble in HFA-134a and HFA-227. The surfactants proposed however may present toxicity problems in use. Extensive and expensive toxicity studies are therefore required before the pharmaceutical regulatory authorities will permit their inclusion in a product intended for human use.
Glaxo Group Limited in WO 96/19968 suggests a pharmaceutical aerosol formulation which comprises particulate medicament, at lease one sugar and a fluorocarbon or hydrogen containing chlorofluorocarbon propellant. The particle size of the sugars used in the formulations are said to be selected using conventional techniques such as milling or micronisation. The suspension stability of the aerosol formulations is said to be particularly impressive.
Other proposals to provide a metered dosed inhaler employing hydrofluoroalkane are found in patent specification no. WO 92/08477 in the name of Glaxo Group Limited and patent specification no. EP 372777 in the name of Riker Laboratories, Inc.
A need therefore exists to provide an aerosol composition suitable for use in for example, an inhaler, comprising a suspension of particulate matter in a propellant, which composition has good dispersion characteristics, a reduced tendency to aggregate and can in use be effectively aerosolised with good valve performance.
It is an object of the present invention to provide an aerosol composition including a particulate material suitable for use in for example an inhaler which composition exhibits both a reduced tendency for the particulate material to aggregate undesirably and ready and homogeneous dispersion of the particulate material, and permits acceptable delivery of the particulate material.
It is a further object of the present invention to provide an additive comprising a particulate material for use in the preparation of such an aerosol composition.
It is a further object of the present invention to provide a container, such as an inhaler, containing such a composition.
It is a further object of the present invention to provide a container, such as metered dose inhaler incorporating a valve dispensing mechanism, containing such a composition, the composition ensuring both good suspension properties and good valve performance over the life of the container.
Further objects of the present invention include a method of preparing a container containing such a composition and a method of administering the composition.
According to a first aspect of the present invention there is provided an aerosol composition comprising a propellant and contained therein a first particulate material comprising particles having a median aerodynamic diameter within the range 0.05 to 11 xcexcm and a second particulate material comprising particles having a median volume diameter within the range 15 to 200 xcexcm.
The propellant is in liquid form during storage of the composition and evaporates in use. The inclusion of a second particulate material having a median volume diameter in the range 15 to 200 xcexcm in combination with the first particulate material having a median aerodynamic diameter in the range 0.05 to 11 xcexcm has unexpectedly been found to enhance dispersion and to reduce particulate aggregation, leading to a reduced risk of irreversible aggregation, whilst still permitting good aerosol performance of the suspension in use. The result is unexpected as prima facie the inclusion of extra insoluble solids had been considered to be inappropriate leading to less desirable aerosol characteristics and poor valve performance due for example to blocking. The present invention can thus permit the delivery of particulate material at a known and consistent concentration.
Although we do not wish to be bound by any theory we believe that the presence of the second particulate material having a median volume diameter in the range 15 to 200 xcexcm reduces the risk of irreversible aggregation of the first particulate material as the larger particles are unable to pack sufficiently close together to permit packing of particles in the primary energy minimum. By xe2x80x9cirreversible aggregationxe2x80x9d we mean aggregation of particles which cannot be dispersed by hand held shaking.
Within the aerosol composition the first and second particulate materials are believed to be present as either a simple admixture or with some or all of the smaller first particulate material particles interacting with the larger particles of the second particulate material. The presence of the second particulate material can thus help to prevent non-specific adsorption of the first particulate material to the inside surface of a container containing the aerosol composition and to break up any aggregates of the first particulate material that may form.
The presence of the second particulate material in the propellant can lead to flocculation i.e. loose association of the suspended particles into a fluffy floc. Flocculation differs from irreversible aggregation in that it occurs in the secondary energy minimum and is dispersible by hand held shaking. Flocculation of the second particulate material can occur in the propellant either in the absence or in the presence of the first particulate material. Where flocculation occurs in the absence of the first particulate material, the equivalent composition containing additionally the first particulate material can surprisingly inhibit the flocculation occurring. Where flocculation of the second particulate material does however occur in the propellant in the presence of the first particulate material it is not detrimental to the present invention as it can be removed by hand held shaking prior to use of the aerosol. It may moreover even be beneficial in preventing irreversible aggregation in the primary energy minimum.
By xe2x80x9cvolume diameterxe2x80x9d is meant the diameter of a sphere having the same volume as the particle. The second particulate material is selected according to its volume diameter as it is the physical bulk of the second particulate material which is believed to be important in determining the properties of the suspension.
By xe2x80x9caerodynamic diameterxe2x80x9d is meant the volume diameter multiplied by the square root of the ratio of the particle density (g cmxe2x88x923) to the density of a particle with same volume diameter having a density of 1 g cmxe2x88x921. The first particulate material is thus selected according to its volume diameter having the stated consideration for its density. In the definition of xe2x80x9caerodynamic diameterxe2x80x9d given above the assumption is made, in keeping with conventional aerosol practice, that the first particulate material can be deemed to be spherical in shape. Moreover, where as is usually the case, the first particulate material has a particle density between about 1 and 2 g cmxe2x88x923 the aerodynamic diameter of the first particulate material is approximately equivalent to its volume diameter
According to another aspect of the present invention there is provided a container containing the aerosol composition according to the present invention, the container including a valve outlet. Suitably the contents of the container are pressurised up to a pressure of 6.893xc3x97105Pa (100 psig). Preferably the container includes a metered valve outlet capable of delivering a measured dose of suspension in the form of an aerosol. Preferably the container is in the form of an inhaler. According to another aspect of the present invention there is provided an inhalation device incorporating the said container.
According to another aspect of the present invention there is provided a method for preparing an aerosol composition comprising:
(a) forming a mixture of a first particulate material comprising particles having a median aerodynamic diameter within the range 0.05 to 11 xcexcm and a second particulate material having a median volume diameter within the range 15 to 200 xcexcm;
(b) dispensing measured portions of respectively said mixture and a propellant into a container, and
(c) scaling the container.
Alternatively all of the ingredients can be admixed prior to dispensing into individual containers.
Suitably the container is pressurised and includes an outlet valve, preferably a metered dose dispensing valve.
The mixture of the first particulate material and the second particulate material permits ready dosing of the mixture into the container due to improved flow characteristics compared to the first particulate material in the absence of the second particulate material. Suitably the mixture is dosed into the container before the propellant. The enhanced dispersion characteristics of the mixture in the added propellant permits the omission of the step of providing a homogeneous suspension prior to dispensing into a container. In keeping with conventional procedures for preparing an aerosol the container can be sealed following the dosing of the mixture into the container, with the propellant being subsequently dosed into the container through for example an outlet valve forming a part of a seal.
According to another aspect of the present invention there is provided a mixture of a first particulate material having a median aerodynamic diameter within the range 0.05 to 11 xcexcm and a second particulate material having a median volume diameter within the range 15 to 200 xcexcm.
According to another aspect of the present invention there is provided a use of a particulate material, for example lactose, having a median volume diameter lying in the range 15 to 200 xcexcm to enhance the dispersion characteristics of a particulate material having a median aerodynamic diameter lying in the range 0.05 to 11 xcexcm in suspension in a propellant.
According to another aspect of the present invention there is provided a method of administering a particulate material to a patient in need thereof comprising the patient inhaling an aerosol comprising vaporised propellant and a mixture of an active agent comprising particles having a median aerodynamic diameter lying in the range 0.05 to 11 xcexcm and a second particulate material comprising particles having a median volume diameter lying in the range 15 to 200 xcexcm. In applying the method, forces generated by vaporisation of the propellant separate particulate active agent from the mixture such that the active agent is available and suitable for lung deposition after inhalation. The method can be applied orally or nasally.
According to another aspect of the present invention there is provided an aerosol composition comprising a mixture of an active agent comprising particles having a median aerodynamic diameter lying in the range 0.05 to 11 xcexcm and a second particulate material comprising particles having a median volume diameter lying in the range of 15 to 200 xcexcm for use in the treatment of respiratory diseases.
Preferably the first particulate material has a median aerodynamic diameter within the range 1 to 10 xcexcm, more preferably within the range 1 to 5 xcexcm. Where the present aerosol composition is employed as an inhaler such preferred ranges are optimum for respiratory delivery.
Preferably the second particulate material has a median volume diameter of more than 20 xcexcm suitably within the range 20 to 125 xcexcm, more preferably within the range 25 to 125 xcexcm, even more preferably within the range 30 to 125 xcexcm, even more preferably still within the range 38 to 125 xcexcm. Preferred ranges may moreover include 45 to 125 xcexcm and 63 to 125 xcexcm.
Suitably the second particulate material is sufficiently soft to ensure that no or minimal damage, for example, such as scratching is sustained by the valve over the lifetime of, for example, a metered dose inhaler. A metered dose inhaler may have the potential to provide in excess of one hundred shots or actuations and ideally needs to be reproducible at a pattern of usage of two shots four times daily. Absence of any significant damage to the valve is essential to ensure that over the lifetime of the container a sufficiently consistent shot or actuation of each dose of homogeneous suspension is provided to ensure appropriate and sufficiently accurate delivery of, for example, medicament as the first particulate material.
A sufficiently soft second particulate material would also reduce the likelihood of valve leakage potentially attributable to particulate material lodging in the valve head and preventing proper reseating of the valve after each use. Preferable the softness of the second particulate material is less than 6.5 Mohs hardness, more preferably less than 5 Mohs hardness, even more preferably less than 4 Mohs hardness and even more preferably less than 3 Mohs hardness. The minimum Mohs hardness is 0. The preferred range is between 2 to 4, the more preferred range is 2 to 3 Mohs hardness.
Performance of the valve in a pressurised container containing the present composition may additionally and/or alternatively be adversely affected by the shape of the particle comprising the second particulate material. Preferably the second particulate material is substantially spheroidal or ellipsoidal. Although we do not wish to bound by any theory, it is postulated that a second particulate material having a generally curved outline will ensure better valve performance due to a reduce likelihood of, for example, scratching of the valve head leading to, possibly, valve leakage and/or inaccurate valve metering. The optimum combination of shape and softness of any second particulate material will, however, be dependent on the material in question and the valve head employed. For example, especially soft second particulate material may yield the necessary good suspension and dispersion properties in the aerosol composition contained in the container prior to use, and yet give no or minimal value damage, even through the particles in the second particulate material are substantially non-spherodial or non-ellipsoidal, for example are in the shape of plates or discs.
The Carr Index is a measure of flow properties of a material in powder form and is substantially dependent on the shape and size of the particles comprising the powder. The Carr Index is defined as:                     tapped density            -              poured density                    tapped density        xc3x97  100  ⁢  %
The Carr Index is measured at 25xc2x0 C. and compares the density of a powder material when poured into a container with the density of the same material in the same container after the container has been tapped and the powder material has settled to a substantially plateau value.
Preferably the Carr Index for particles comprising the second particulate material and having a population predominantly (i.e.  greater than 50%) more than 100 xcexcm in diameter is less than 14%, more preferably less than 12%, even more preferably less than 10%.
Preferably the Carr Index for particles comprising the second particulate material and having a population predominantly (i.e.  greater than 50%) less than 100 xcexcm in diameter is less than 28%, more preferably less than 26%, even more preferably less than 24%.
Preferably the Carr Index for particles comprising the second particulate material and having a population predominantly (i.e.  greater than 50%) less than 40 xcexcm in diameter is less than 35%, more preferably less than 33%, even more preferably less than 31%.
Preferably the Carr Index for particles comprising the second particulate material and having a population predominantly (i.e.  greater than 50%) less than 20 xcexcm in diameter is less than 65%, more preferably less than 63%, even more preferably less than 61%.
Preferably the weight ratio of the first particulate material to the second particulate material lies in the range 1:0.1 to 1:500, the weight being that of the first particulate material and the weight of the second particulate material admixed with the propellant and thus includes any material dissolved in the propellant. More preferably the weight ratio of the first particulate material to the second particulate material lies in the range 1:1 to 1:200, even more preferably within the range 1:10 to 1:100, even more preferably within the range of 1:25 to 1:67. The actual ratio selected for any particular suspension will depend inter alia on the solubility of each of the first and second particulate materials in the propellant, the dosage or usage requirements of the particulate materials and the extent of any interaction between the first particulate material and the second particulate material. An alternative preferred range of the weight ratio of first to second particulate material is 1:5 to 1:50.
The actual amount and size of each particulate material used will depend inter alia on the solubility of each particulate material in the propellant and the type and dose of each particulate material required. Suitably however the aerosol composition comprises 80 to 99.999 wt % propellant, more suitably 90 to 99.9 wt % propellant. The total weight of particulate material employed, measured as including dissolved and undissolved material, is thus suitably 20 to 0.001 wt % with respect to the total weight of the composition, more preferably 10 to 0.1 wt % with respect to the total weight of the composition. The concentration of the first particulate material in the composition, including dissolved and undissolved material, preferably lies in the range 1 to 0.0001 wt %, more preferably in the range 0.5 to 0.005 wt % with respect to the total weight of the composition.
Each of the first and second particulate materials may be partially soluble in the propellant. Preferably the solubility of the first particulate material in the propellant does not exceed 49.9 wt % with respect to the total weight of the substance comprising the first particulate material present. More preferably the solubility of the first particulate material in the propellant does not exceed 10 wt %, even more preferably 1.0 wt % with respect to the total weight of first particulate material present.
Preferably the solubility of the second particulate material in the propellant does not exceed 49.9 wt % with respect to the total weight of the substance comprising the second particulate material present. More preferably the solubility of the second particulate material does not exceed 10 wt %, even more preferably 1.0 wt % with respect to the total weight of the second particulate material present. Low solubility of each of the first particulate material and the second particulate material is preferred in order to avoid stability problems such as the risk of particle growth due to Ostwald ripening.
Preferably the ratio of the density of the second particulate material to the density of the propellant lies in the range 0.6:1 to 1:1.6. Too large a density difference between the density of the second particulate material and the density of the propellant is preferably avoided. The optimal density difference can be ascertained in each instance, particularly having regard to the ambient temperature effecting the density of the propellant and any tendency of the second particulate material to flocculate in the presence of the first particulate material. When not equal to the density of the propellant the density of the first particulate material and the density of the second particulate material are in some instances suitably both either more than or less than the density of the propellant. Should the first and second particulate materials exhibit any tendency to sediment or cream (i.e. float) their uniform dispersion in the propellant can thus be more readily achieved.
The substance comprising the second particulate material is suitably chemically unreactive with respect to the first particulate material. The present aerosol composition can be in the form of a pharmaceutical composition. Where the first particulate material is a medicament, the second particulate material preferably does not modify the biopharmaceutical profile of the medicament comprising the rust particulate material. The second particulate material can comprise one or more active or inactive agents or a mixture thereof, for example it can comprise one or more pharmacologically inert substances, one or more pharmacologically active substances, one or more flavour imparting substances or a mixture thereof. Where the present aerosol composition is intended for use as an inhaler, the second particulate material can for example comprise a pharmacologically active substance for oral administration.
Where the first particulate material is a medicament, the second particulate material should be acceptable for administration to a human. Preferably it will be a substance which already possesses regulatory approval and has a desirable safety profile. For example where the present aerosol composition is intended for use as an inhaler the second particulate material may already possess regulatory approval for use in pulmonary administration. The second particulate material selected should preferably be relatively inexpensive and readily available.
Suitable substances for use as the second particulate material in at least an inhaler may be selected from carbohydrates such as sugars, mono-, di-, tri-, oligo- and poly-saccharides and their reduced forms such as sorbitol; from amino acids, di-, tri-, oligo- and poly-peptides and proteins; and from physiologically acceptable derivatives, forms, salts and solvates thereof; and from mixtures thereof. Preferably the second particulate material is selected from lactose, glucose and leucine and mixtures thereof. The material can be in any appropriate form, for example lactose can be xcex1-lactose, xcex2-lactose, anhdrous lactose, amorphous or any form of lactose or any mixture thereof. Leucine and spray dried lactose are especially preferred where valve performance may be of importance as they are each relatively soft. Spray dried lactose additionally is substantially spheroidal and may be preferred where valve performance is of importance.
Where the first particulate material is a particulate medicament suitable for oral or nasal inhalation and the aerosol composition is intended for use as an inhaler, examples of suitable particulate medicaments for use in the treatment and prevention of asthma and other conditions associated with reversible airways obstruction include either alone or in any combination:
(i) salbutamol, salbutamol sulphate, mixtures thereof and physiologically acceptable salts and solvates thereof,
(ii) terbutaline, terbutaline sulphate, mixtures thereof and physiologically acceptable salts and solvates thereof,
(iii) beclomethasone dipropionate and physiologically acceptable solvates thereof,
(iv) budesonide and physiologically acceptable solvates thereof,
(v) triamcinolone acetonide and physiologically acceptable solvates thereof,
(vi) iprawtopium bromide and physiologically acceptable salts and solvates thereof, and
(vii) corticosteriod or bronchodilator.
Other examples of particle medicaments suitable for oral or nasal inhalation by means of the present aerosol composition include:
(viii) peptides, proteins, nucleic acids and derivatives thereof for use in the treatment and prevention of disease states,
(ix) insulin, calcitonin, growth hormone, lutenising hormone release hormone (LHRH), leuprolide, oxytocin and physiologically acceptable salts and solvates thereof for use in the treatment and prevention of disease states including diabetes, and
(x) any pharmacologically active particulate medicament having a median aerodynamic diameter within the range 0.05 to 11 xcexcm administered in the form of an aerosol.
Further examples of appropriate medicaments may additionally be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; anti-infectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furoate or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, pbenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, or (xe2x88x92)4-amino-3,5-dichlor-xcex1[[[6-[2-(2-pyridinyl)ethoxy] hexyl]methyl] benzenemethanol; diuretics, e.g., amiloride; anticholinergies, e.g., ipratropium, iotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides e.g., insulin or glucagon. It will be clear to a person skilled in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimise the activity and/or stability of the medicament.
Preferred medicaments are selected from albuterol salineterol, fluticasone propionate and beclometasone dippropionate and salts or sovates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol.
Medicaments can also be delivered in combinations. Preferred formulations containing combinations of active ingredients contain salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate).
The dosage requirements for any one medicament will be those conventionally employed in inhalers. For example where the first particulate material is salbutamol for use in relation to asthma the inhaler is employed as required, usually 1 or 2 actuations (i.e. puffs) between 0 and 4 times per day, with a single metered dose comprising 100 micrograms of salbutamol in a volume of metered liquid propellant between 20 and 150 xcexcl.
The propellant is preferably selected from chlorofluorocarbons, from hydrofluorocarbons and from mixtures thereof. When the propellant is a chlorofluorocarbon such as CFC-11, CFC-12, CFC-114 the present invention can provide a suspension that obviates the need for the addition of unpalatable, or possibly even mildly toxic, surfactant. Alternatively the propellant can comprise hydrofluoroalkane such as 1,1,1,2-tetrafluoroethane (HFA-134a), 1,1,1,2,3,3,3-heptafluoropropane (HFA-227) and mixtures thereof. The combination of the first particulate material with the second particulate material both reduces the risk of the first particulate material aggregating undesirably and enhances the dispersement of the particulate medicament in the propellant. In manufacturing individual units of the suspension the increased dispersibility provided by the present invention obviates the need to prepare an initial bulk suspension by a homogenisation step. The combination of the first particulate material and the second particulate material can be readily wetted by and dispersed in HFA propellants in the absence of surfactant or added co-solvent. The suitable dispersion characteristics in HFA displayed by the presently provided combination of particulate materials permits its initial dispersion and any redispersion required following sedimenting or creaming with a small energy input, e.g. hand held shaking.
The present suspension can optionally contain any additional appropriate ingredients, for example pharmacologically acceptable excipients such as a surfactant, flavouring, buffer and preservatives in conventional acceptable amounts.